SDH-Deficient GIST
Gastrointestinal Stromal Tumor (GIST) is the most common sarcoma with approximatley 5,000 new cases diagnosed annually in the U.S. Among these, succinate dehydrogenase (SDH)-deficient GISTs comprise only about 5-7.5%. SDH-deficient patients may experience only GIST tumors. However, they can also present in the setting of Carney-Stratakis Dyad (Familial paraganglioma and GIST) or Carney’s Triad (paraganglioma/pheochromocytoma, GIST, and pulmonary chondroma). At present, all FDA-approved anti-GIST therapies are predicated primarily upon targeting KIT “oncogene-addiction”. However, SDH-deficient GISTs frequently have primary imatinib-resistance, while sunitinib and regorafenib have limited efficacy. Drugs such as linsitinib and vandetanib, targeting pathways upregulated in SDH-deficient GIST, have also failed to show sustained benefit for most patient with this disease. Thus, targeting SDH-deficient GIST in a novel fashion is of critical importance. One of the major impediments to SDH research is the lack of a broadly applicable model of SDH-deficient GIST (i.e., cell line, mouse model, patient-derived xenograft, or in silico models) that could be used to study the effects of anticancer compounds and drugs on tumor cells.
In accordance with its Mission to advance treatment for SDH-deficient cancers, the SDH-deficient GIST Research Advocates (SDH-RA) has been been working to facilitate transfer of SDH-deficient tumor samples to researchers and to provide a portal for those wishing to donate to SDH-deficient GIST research. We have identified a need for research funding by the team of Dr. Jason Sicklick and Dr. Pablo Tamayo.
The goal of Dr. Sicklick and Tamayo's research is to develop specific therapies for SDH-deficient GIST (and potentially, subsequently for SDH-deficient paraganglioma, pheochromocytoma, and renal cell carcinomas). Research funding is needed for continued efforts including establishment of an SDH-deficient cell line and development of mouse models to expand knowledge of the characterization of pathways that drive self-renewal and indentification of compounds that will inhibit SDH-deficient GIST cell survival and enhance patient oucomes.
Current treatment strategies for GIST typically utilize a “one size fits all” approach, in which every GIST patient is treated with the same regimen of surgery, if applicable, and imatinib. This strategy fails to take into account the underlying genetic and molecular differences between different types of GIST. As a result, SDH-deficient GIST patients are frequently treated with TKIs with a high rate of primary drug resistance. Drs. Sicklick & Tamayo propose to model and characterize the metabolic and molecular properties of SDH-deficient GIST cells in order to develop treatment strategies. They believe that this approach could result in more favorable outcomes for all SDH-deficient GIST patients, including those with paragangliomas caused by Carney-Stratakis Dyad and Carney Triad.
Dr. Jason Sicklick, MD (Principal Investigator) is an Associate Professor of Surgery and Surgical Oncology at the Moores UCSD Cancer Center. His lab uses cells lines, as well as transgenic and xenograft models of GIST to understand the biology of the disease and to test novel approaches to overcome drug-resistance. Dr. Sicklick will be responsible for the overall experimental activity of the SDH-deficient GIST study and will oversee communication of the research team. He will supervise all aspects of the proposed research, including data analysis and interpretation.
Dr. Pablo Tamayo, PhD (Co-Principal Investigator) is a Professor in the UCSD School of Medicine and co-director of the UCSD Moores Cancer Center Genomics and Computational Biology group. He have over 24 years of post-Ph.D. experience in computational methods, probability and statistics, data analysis, machine learning, computational biology and cancer research.
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